Natural infection with Toxoplasma gondii is by the peroral route. Thus, initial invasion by the parasite is through the gut of the host. Many tachyzoites are then likely to be trapped in the liver. Therefore, it is likely that gut-associated lymphoid tissue (GALT) (intraepithelial lymphocytes, lamina propria lymphocytes, lymphocytes in the Peyer's patches, mesenteric lymph nodes) and the liver play critical roles in resistance against peroral infection with T. gondii. However, information regarding the immune response in the gut and liver during T. gondii infection is lacking. Recently, I found a critical role of gamma/delta T cells in the intraepithelial lymphocytes of the small intestines and T cells in the lover in prevention of proliferation of tachyzoites in these organs during the early stage of peroral infection. In addition, I also found that alpha/beta T cells are protective against peroral infection with a less virulent strain but detrimental in peroral infection with a more virulent strain of T. gondii. In relation to genetic susceptibility of mice, my preliminary data reveal a critical role of T cells in development of necrosis in the small intestines which occurred only in the susceptible mice during the early stage of peroral infection. I hypothesize that the functions of T cells of the GALT and liver during the early stage of peroral infection with T. gondii are critical in determining the outcome of the infection. The overall specific aim of this proposal is to analyze the function of T cells generated in the gut and liver during the early stage of peroral infection with T. gondii in mice and to determine the role of T cells in these organs in resistance against and pathogenesis of toxoplasmosis in relation to the virulence of the parasite and genetic susceptibility of the host. These long term objectives will be addressed by gaining information on: 1) changes in populations of T cell subsets in the GALT and liver. 2) Identification of T cell subset(s) responsible for protective or "harmful" immune responses. 3) cytokine production and cytotoxic activity of the T cell subset(s) responsible for the protective or "harmful" immune responses. 4) the role of cytokine(s) in protective of "harmful" activity of T cell subset(s). The data generated from these studies will contribute to the long term aims of this proposal by gaining a better understanding of the roles and functions of T cells in the GALT and liver in resistance against T. gondii and in the pathogenesis of toxoplasmosis in relation to the virulence of the parasite and genetic susceptibility of the host.